The present invention relates to a process for preparing substituted indoles of the formula (I), in which substituted 2-alkynylanilines are cyclized in a polar aprotic solvent with the aid of a suitable alkali metal compound.
Simple, low-cost indole syntheses are of great general interest, since the indole structure is found in numerous natural products and in particular in pharmacologically active substances. To date, there are a number of principal routes leading to the desired indole derivatives.
Intramolecular addition of amino groups to a carbon-carbon triple bond with formation of indole derivatives is a reaction known from the literature. The reaction can be catalyzed, for example, by palladium complexes. This is described, inter alia, in the publication by K. Utimoto et al. in Tetrahedron Letters 29 (1992), 3915 ff.
Other publications disclose the use of molybdenum(0) compounds in these cyclization reactions. This can be found in the publications by F. E. McDonald et al. in Tetrahedron Letters 38 (1997), 7687 ff. and in Chem. Eur. J. 5 (1999), 3103 ff.
In a variant described in a plurality of publications by S. Cacchi et al., for example in Tetrahedron Letters 33 (1992), 3915 ff., Synlett 1997, 1393 ff., Tetrahedron Letters 50 (1994), 437 ff., it is possible to use, instead of the alkynylanilines, the corresponding trifluoroacetamides, the catalysts used here again being palladium complexes.
The synthesis of substituted indoles is furthermore described by Yamanaka et al. in Heterocycles 24 (1986), 31/32. Here, alkynylcarbanilates are cyclized in the presence of Na ethoxylate, and the N-bonded C(O)O-alkyl unit is removed by hydrolysis. This cyclization reaction does not work if the starting material used is a 2-alkynylaniline.
However, in all of these reactions it is frequently necessary to heat the reaction mixture to relatively high temperatures, and frequently, long reaction times are additionally required to achieve acceptable yields. These harsh reaction conditions, which are generally required, strongly restrict, inter alia, the range of the various functionalities which can be present in the 2-alkynylanilines.
It is an object of the present invention to provide a process which allows a simple preparation of the substituted indoles, with good yields and using short reaction times and low reaction temperatures. The process should furthermore permit the synthesis of substituted indoles having a large number of different substituents.
We have found that this object is achieved by a process for preparing compounds of the indole type of the formula 
in which A is a hydrocarbon radical which, together with the carbons to which it is attached, forms a substituted or unsubstituted mono- or polycyclic aromatic system which may contain one or more heteroatoms from the group consisting of N, O and S, and
R1, R2 independently of one another are H, a saturated, linear or branched aliphatic C1-C20-hydrocarbon radical, an unsaturated, linear or branched aliphatic C2-C20-hydrocarbon radical, a saturated or unsaturated, unsubstituted or alkyl-substituted cycloaliphatic C3-C20-hydrocarbon radical or an aromatic C5-C20-hydrocarbon radical, where these radicals may contain in their molecular skeleton one or more heteroatoms from the group consisting of the halogens, N, P, O, S, Si, Sn and B and may be substituted or unsubstituted, by cyclization of alkynylaminoaromatics of the formula 
in which R1 and R2 are as defined in formula (I) and R1, R2 or A may be attached to an organic or inorganic carrier, which comprises carrying out the reaction in a polar aprotic ion-solvating solvent in the presence of a suitable compound of Na, K, Rb or Cs.
We have found that the process according to the invention permits access to a large number of compounds of the indole type of a range which has not been possible with the processes of the prior art. By using the alkali metal compounds which are employed in the process according to the invention, it is possible to prepare indole derivatives which may have virtually any customary substituents R1, R2. In the individual case, the accessibility of certain substituted indole derivatives depends on the influence of certain parameters. These are, for example, steric interactions between the individual substituents present, and possibly also the aromatic system is of the indole derivative. The range of the different substituents R1 and R2 and of the substituents which may be present on the aromatic system of the formula (I) is enormously wide and comprises virtually all compound classes and functional groups which are included in the definition given above.
In a preferred embodiment of the present invention, the substituents R1 and R2 independently of one another are selected from the group consisting of H, linear and branched C1-C12-alkyl groups, linear and branched C2-C12-alkenyl groups, C3-C8-cycloalkyl groups, C3-C8-cycloalkenyl groups, C5- and C6-heterocycles having one or more ring atoms selected from the group consisting of N, O and S and mono- or bicyclic aromatics having one or more ring atoms selected from the group consisting of N, O and S.
Both in the preferred and the not preferred embodiments, the substituents R1 and R2 may have one or more substituents in their molecular skeleton.
Examples of preferred substituents are amino and nitro groups, halogens, hydroxyl and ether groups, thiol groups, thioether groups, amide and ester groups, sulfaryl groups and sulfoxide groups.
The aromatic system in the compounds of the formula (I) can be a mono- or polycyclic aromatic which comprises exclusively carbon and hydrogen or which may have one or more heteroatoms selected from the group consisting of N, O and S.
The aromatic system is preferably a mono- or bicyclic aromatic. More preferably, the aromatic system is a C5-heterocycle or a benzene or naphthalene derivative which may contain one or more of the heteroatoms N, O and S mentioned, examples being benzene and naphthalene, aza-, diaza- and triazabenzene, aza-, diaza- and triazanaphthalene, thiophene and furan.
In the most preferred embodiment of the present invention, the aromatic system in the formula (I) is selected from the group consisting of benzene, naphthalene, pyridine, pyrazine, pyrimidine, quinoline, thiophene and furan.
Both in the preferred and the not preferred embodiments, the aromatic system may have one or more substituents which, similarly to the substituents R1 and R2, may vary extremely. Non-limiting examples of such substituents are alkanes and alkenes which are either unsubstituted or may carry customary substituents, for example halogens, amines, nitro groups, ether and hydroxyl groups or thiol- and thioether groups. Further examples of substituents on the aromatic system are amino and nitro groups, halogens, hydroxyl and ether groups, thiol groups, sulfaryl groups, sulfoxide groups, thioether groups, amide and ester groups.
In one embodiment of the present invention, the synthesis of the indole derivatives (I) can be carried out by attaching the alkynylaminoaromatic (II) used as starting material to an organic or inorganic carrier and immobilizing it. These carriers are known to the person skilled in the art and correspond to the customary carrier materials used, for example, for solid-phase peptide synthesis or for fixing transition metal catalyst systems. Examples are Merrifield resin, 4-(2xe2x80x2, 4xe2x80x2-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucyl-methylbenzhydrylamino-(divinylbenzene-crosslinked polystyrene) resin, also known under the name Rink-MBHA resin, which is generally used after deprotection by removal of the 9-fluorenylmethoxycarbonyl-(Fmoc) group, and the carrier resin which is commercially available under the name trityl chloride resin, if appropriate after appropriate modification.
These carriers are either bonded to the aromatic system of the starting materials (II), or the substituent R1 is attached to the carrier. If appropriate, the carrier may have suitable spacer groups which are attached to the starting material. Following the synthesis of the corresponding indole compound, the bond between the carrier and the target molecule is broken in a customary manner known to the person skilled in the art, for example by cleaving the bond between carrier and spacer group using trifluoroacetamide.
A further embodiment of the present invention allows the synthesis of compounds (I) in which the aromatic system, which is fused with the pyrroline unit, forming a bicyclic indole unit, is fused with a further pyrroline unit, forming a tricyclic bifunctional indole. To this end, the starting material (II) used is a compound which does not only have one acetylene function and one amino function in a vicinal position, but in each case two of these functions.
The synthesis element according to the invention can also be widened such that the resulting indole does not only contain 2 pyrroline units, but 3 or even more of these units. To this end, a starting material (It) is used which contains 3 or even more vicinal acetylene and amino functions.
The synthesis according to the invention is carried out using a suitable compound of Na, K, Rb or Cs, which is employed in combination with a polar aprotic solvent having ion-solvating properties. By using these solvents, it is possible to increase the electrophilicity of the ions of the metals mentioned such that the cyclization according to the invention can be carried out under mild conditions.
These polar aprotic ion-solvating solvents are known to the person skilled in the art, examples being N-methylpyrrolidone (NMP), N-butylpyrrolidone (NBP), dimethyl sulfoxide (DMSO), sulfolane (tetrahydrothiophene 1,1-dioxide), dimethylformamide (DMF), tetrahydrofuran (THF), ethers, hexamethylphosphoric triamide (HMPT) and N,Nxe2x80x2-dimethylpropyleneurea.
Examples of suitable ethers are ethers which can be obtained from ethylene oxide and/or propylene oxide. This can be ethylene glycol and propylene glycol ethers, oligo- or polyethylene glycol, oligo- and polypropylene glycol and ethylene glycol/propylene glycol copolymers or block copolymers, such as, for example, the compounds known under the names glyme, diglyme, triglyme or the names Pluronic(copyright) and Pluriol(copyright) (from BASF AG). It is also possible to use ethers which are prepared by condensing ethylene oxide and/or propylene oxide with polyvalent amines, for example the products available under the names Tetronic(copyright) and Lutensol(copyright) (in each case from BASF AG).
It is also possible to use the respective ethers, for example the methyl ethers, of all of the abovementioned ethylene glycol and propylene glycol ethers, which, for example in the case of Pluronic(copyright), Pluriol(copyright) and Tetronic(copyright), may still have free terminal hydroxyl groups. Suitable ethers are also crown ethers and cryptands.
These solvents can be used on their own, as a mixture or as additive to other solvents. They have to be added in an amount which is sufficient to achieve the desired ion solvation and thus the required reactivity.
The compounds of Na, K, Rb and Cs which are employed are those which dissociate well in the solvents mentioned and whose ions are sufficiently solvated by these solvents. Examples of suitable compounds of the alkali metals quoted are hydroxides, hydrides, alkoxides, amides and aminopropylamides.
Particularly suitable compounds are hydroxides and alkoxides.
Among the abovementioned metals Na, K, Rb and Cs, the best reactivities are obtained when K and Cs are used, and their use is preferred. The alkali metal compounds used according to the invention can be employed in stoichiometric or superstoichiometric amounts, but also in catalytic amounts. The minimum amount of alkali metal compounds is about 5 mol %; however, it is also possible to use amounts of up to 250 mol %, based on the substrate. The reaction temperatures required for the process according to the invention are about  less than 100xc2x0 C. The process according to the invention is preferably carried out at temperatures of about 20-60xc2x0 C., most preferably of about 20-40xc2x0 C. The reaction times are from about 2 to 20 hours, preferably from 2 to 8 hours. The starting materials (II) are obtained by the Sonogashira reaction (see K. Sonogashira et al., Synthesis 1980, 627 ff., K. Sakomoto, Synthesis 1983, 312 ff., G. C. Fu et al., Angew. Chem. Int. Ed. Engl. 38 (1999), 2411 ff.) from the corresponding 2-iodo- or 2-bromoanilines by reaction with 1-alkynes. If the process according to the invention is carried out on a carrier, in solid phase, the corresponding iodo- or bromoaniline is, prior to the Sonogashira coupling, fixed to the carrier using methods known to the person skilled in the art. The invention is now illustrated by the examples below.